Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

PLoS biology ·Vol. 9 卷 ·Vol. 11 Iss. ·2012-03-19

Maxwell Christopher A, Benítez Javier, Gómez-Baldó Laia, Osorio Ana, Bonifaci Núria, Fernández-Ramires Ricardo, Costes Sylvain V, Guinó Elisabet, Chen Helen, Evans Gareth J R, Mohan Pooja, Català Isabel, Petit Anna, Aguilar Helena, Villanueva Alberto, Aytes Alvaro, Serra-Musach Jordi, Rennert Gad, Lejbkowicz Flavio, Peterlongo Paolo, Manoukian Siranoush, Peissel Bernard, Ripamonti Carla B, Bonanni Bernardo, Viel Alessandra, Allavena Anna, Bernard Loris, Radice Paolo, Friedman Eitan, Kaufman Bella, Laitman Yael, Dubrovsky Maya, Milgrom Roni, Jakubowska Anna, Cybulski Cezary, Gorski Bohdan, Jaworska Katarzyna, Durda Katarzyna, Sukiennicki Grzegorz, Lubiński Jan, Shugart Yin Yao, Domchek Susan M, Letrero Richard, Weber Barbara L, Hogervorst Frans B L, Rookus Matti A, Collee J Margriet, Devilee Peter, Ligtenberg Marjolijn J, Luijt Rob B van der, Aalfs Cora M, Waisfisz Quinten, Wijnen Juul, Roozendaal Cornelis E P van, , , Easton Douglas F, Peock Susan, Cook Margaret, Oliver Clare, Frost Debra, Harrington Patricia, Evans D Gareth, Lalloo Fiona, Eeles Rosalind, Izatt Louise, Chu Carol, Eccles Diana, Douglas Fiona, Brewer Carole, Nevanlinna Heli, Heikkinen Tuomas, Couch Fergus J, Lindor Noralane M, Wang Xianshu, Godwin Andrew K, Caligo Maria A, Lombardi Grazia, Loman Niklas, Karlsson Per, Ehrencrona Hans, Wachenfeldt Anna von, , Barkardottir Rosa Bjork, Hamann Ute, Rashid Muhammad U, Lasa Adriana, Caldés Trinidad, Andrés Raquel, Schmitt Michael, Assmann Volker, Stevens Kristen, Offit Kenneth, Curado João, Tilgner Hagen, Guigó Roderic, Aiza Gemma, Brunet Joan, Castellsagué Joan, Martrat Griselda, Urruticoechea Ander, Blanco Ignacio, Tihomirova Laima, Goldgar David E, Buys Saundra, John Esther M, Miron Alexander, Southey Melissa, Daly Mary B, , Schmutzler Rita K, Wappenschmidt Barbara, Meindl Alfons, Arnold Norbert, Deissler Helmut, Varon-Mateeva Raymonda, Sutter Christian, Niederacher Dieter, Imyamitov Evgeny, Sinilnikova Olga M, Stoppa-Lyonne Dominique, Mazoyer Sylvie, Verny-Pierre Carole, Castera Laurent, de Pauw Antoine, Bignon Yves-Jean, Uhrhammer Nancy, Peyrat Jean-Philippe, Vennin Philippe, Fert Ferrer Sandra, Collonge-Rame Marie-Agnès, Mortemousque Isabelle, , Spurdle Amanda B, Beesley Jonathan, Chen Xiaoqing, Healey Sue, , Barcellos-Hoff Mary Helen, Vidal Marc, Gruber Stephen B, Lázaro Conxi, Capellá Gabriel, McGuffog Lesley, Nathanson Katherine L, Antoniou Antonis C, Chenevix-Trench Georgia, Fleisch Markus C, Moreno Víctor, Pujana Miguel Angel

Abstract

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Article Info

Journal

PLoS biology

Abbr.

PLoS Biol

ISSN

1544-9173

Published

2012-03-19

Indexed

2011-11-23

Updated

2016-12-05

Language

English

Country/Region

United States

NLM ID

101183755

External Links

PubMed source View journal details

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Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

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